© 1995 American Heart Association, Inc.
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[Ca2+]i Inhibition of K+ Channels in Canine Pulmonary Artery
Novel Mechanism for Hypoxia-Induced Membrane Depolarization
From the Department of Physiology, University of Nevada School of Medicine, Reno.
Correspondence to Dr Joseph R. Hume, Department of Physiology, University of Nevada School of Medicine, Reno, NV 89557-0046.
Abstract Experiments were performed on smooth muscle cells isolated from canine pulmonary artery to identify the type of K+ channel modulated by hypoxia and examine the possible role of [Ca2+]i in hypoxic K+ channel inhibition. Whole-cell patch-clamp experiments revealed that hypoxia (induced by the O2 scavenger, sodium dithionite) reduced macroscopic K+ currents, an effect that could be prevented by strong intracellular buffering of [Ca2+]i. The inhibitory effects of hypoxia were mimicked by acute exposure of cells to caffeine and could be prevented by caffeine pretreatment, suggesting an important obligatory role of [Ca2+]i in hypoxic inhibition of K+ currents. Exposure of cells to low concentrations of 4-aminopyridine (4-AP, 1 mmol/L) prevented hypoxic inhibition of macroscopic K+ currents, whereas low concentrations of tetraethylammonium were without effect, suggesting that the target K+ channel inhibited by hypoxia is a voltage-dependent delayed rectifier K+ channel, which is inhibited by [Ca2+]i. Hypoxia failed to consistently modify the activity of large-conductance (118 picosiemens [pS] in physiological K+) Ca2+-activated K+ channels in inside-out membrane patches but reduced open probability of smaller-conductance (25-pS) delayed rectifier K+ channels in cell-attached membrane patches. In inside-out membrane patches, 1 µmol/L Ca2+ added to the cytoplasmic surface significantly reduced open probability of small-conductance (25-pS) 4-AP–sensitive delayed rectifier K+ channels. Whole-cell current measurements using symmetrical K+ to increase driving force for small currents active near the cell's resting membrane potential revealed the presence of a 4-AP–sensitive K+ current that activated near -65 mV and was inhibited by hypoxia. Simultaneous measurements of changes in [Ca2+]i, using the Ca2+ indicator indo 1, and membrane potential revealed that hypoxia causes an initial rise of [Ca2+]i, which precedes hypoxia-induced membrane depolarization. It is concluded that in canine pulmonary arterial cells an early key event in hypoxic pulmonary vasoconstriction is release of Ca2+ from caffeine-sensitive intracellular Ca2+ stores, which causes inhibition of delayed rectifier K+ channels and membrane depolarization, possibly leading to subsequent activation of Ca2+ entry through voltage-dependent Ca2+ channels.
Key Words: pulmonary artery • hypoxia • K+ channels
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